Alcohol abuse is common in the HIV infected population, and several studies have identified this behavior as a risk factor for poor disease outcome. The widespread clinical use of highly effective anti-retroviral therapy (ART) has dramatically improved HIV disease survival, but studies demonstrate that alcohol-abusing patients do not experience the same clinical benefit as the general HIV population. The rhesus macaque model of SIV Infection has proven an excellent model for studying the pathogenesis of HIV disease, and work in this model confirms a detrimental effect of chronic alcohol consumption on survival from SIV infection. Given the ability to directly control for multiple confounding factors (including medication compliance), the study of alcohol's effects on antiretroviral efficacy and toxicity are ideally performed in the macaque model. The gastrointestinal tract has been identified as a key organ in which rapid, severe, and persistent CD4+ T cell depletion occurs in HIV/SIV disease, and recovery of gut CD4+ T cells is a excellent prognostic finding during the course of ART. Because alcohol and SIV disease each affect gut T cell populations and increase mucosal inflammation and permeability, there is ample rationale to support our hypotheis that chronic binge alcohol consumption in SIV-infected macaques increases intestinal inflammation and permeability, resulting in higher levels of mucosal and systemic immune activation and impairment of both mucosal CD4+ T cell recovery and SlV-specific cytotoxic T lymphocyte responses during anti-retroviral therapy. Using this well-established macaque/alcohol/SIV model, our Specific Aims are to test the predictions that chronic alcohol consumption will: 1) impair recovery of intestinal memory CD4+ T cells during ART of SIV infection, 2) alter the phenotype and function of SlV-specific mucosal CD8+ T cell responses during ART therapy, and 3) alter intestinal barrier function, which promotes SIV/HIV replication and disease progression. These studies will facilitate a better understanding of the biologic impact of alcohol on drug treatment for HIV infection and are directly responsive to the critical goals of the Trans-NIH Plan for HIV-Related Research.